A decline in endocrine function, an increase in serum cholesterol levels and an increase in atherosclerotic vascular disease are all associated with aging. Cholesterol synthesis and quite possibly degradation as well, is regulated by hormones, such as insulin, glucagon, thyroid hormones and glucocorticoids. Thus the objective of the proposed investigation is to determine whether changes in the rates of cholesterol biosynthesis and cholesterol degradation (via conversion to bile acid) occur as a function of age and whether these changes are due to alterations in the hormonal regulation of these processes. For this investigation, rats of varying ages will be used. Since changes in the rates of cholesterol biosynthesis and degradation are due to changes in HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities, respectively, the activities of these key enzymes will be determined in these rats. Should changes in the activities of these enzymes be observed in older rats, we would then seek the mechanism by which these changes are mediated. The possibility that older rats may not be as responsive to hormones with respect to the stimulation of these enzymes will be examined. A larger dose of hormone or a longer lag period may be needed in older animals in order to observe the same degree of response. It is also conceivable that older rats will not have as great a maximal response to hormones. An alteration in the hormonal regulation of these enzymes in aged rats may give rise to a decreased turnover of cholesterol and a subsequent increase in serum levels. The proposed studies should provide information as to whether altered hormone function in the aged is responsible for certain observed pathological changes. BIBLIOGRAPHIC REFERENCES: Lakshmanan, M. R., Dugan, R.E., Nepokroeff, C. M., Ness, G. C. and Porter, J. W. (1975). Regulation of Rat Liver, beta-Hydroxy-beta-Methylglutaryl Coenzyme A Reductase Activity and Cholesterol Levels of Serum and Liver in Various Dietary and Hormonal States. Arch. Biochem. Biophys. 168, 89-95.